Certain 4-piperidine- and piperazinoalkyl-2-phenyl imidazole derivatives; dopamine receptor subtype specific ligands

ABSTRACT

Disclosed are compounds of the formula   &lt;IMAGE&gt;   wherein R1 represents optionally substituted aryl, heteroaryl, arylalkyl, or cycloalkyl groups; X, Z, and Y are optionally substituted nitrogen or carbon atoms; R3 and R4 are organic or inorganic substituents which may together form ring structures; m is zero, one or two; and R5 and R6 are are organic or inorganic substituents; and the pharmaceutically acceptable addition salts thereof, which compounds are highly selective partial agonists or antagonists at brain dopamine receptor subtypes or prodrugs thereof and are useful in the diagnosis and treatment of affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism.

This application is a continuation of U.S. patent application Ser. No.08/344,154, filed Nov. 23, 1994, now abandoned, which is acontinuation-in-part of U.S. patent application Ser. No. 08/081,317,filed Nov. 8, 1993, now U.S. Pat. No. 5,428,164, which is a nationalphase of PCT/US91/09816, filed Dec. 23, 1991, which is acontinuation-in-part of U.S. patent application Ser. No. 07/635,256,filed Dec. 28, 1990, now U.S. Pat. No. 5,159,083.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain 4-aminomethyl-2-substituted imidazoleand 2-aminomethyl-4-substituted derivatives which selectively bind tobrain dopamine receptor subtypes. This invention also relates topharmaceutical compositions comprising such compounds. It furtherrelates to the use of such compounds in treating affective disorderssuch as schizophrenia and depression as well as certain movementdisorders such as Parkinsonism. Furthermore, compounds of this inventionmay be useful in treating the extrapyramidyl side effects associatedwith the use of conventional neuroleptic agents. The interaction ofthese aminomethylimidazole derivatives of the invention with dopaminereceptor subtypes is described. This interaction results in thepharmacological activities of these compounds.

2. Description of the Related Art

Schizophrenia or psychosis is a term used to describe a group ofillnesses of unknown origin which affect approximately 2.5 millionpeople in the United States. These disorders of the brain arecharacterized by a variety of symptoms which are classified as positivesymptoms (disordered thought, hallucinations and delusions) and negativesymptoms (social withdrawal and unresponsiveness). These disorders havean age of onset in adolescence or early adulthood and persist for manyyears. The disorders tend to become more severe during the patient'slifetime and can result in prolonged institutionalization. In the UnitedStates today, approximately 40% of all hospitalized psychiatric patentssuffer from schizophrenia.

During the 1950's physicians demonstrated that they could sucessfullytreat psychotic patients with medications called neuroleptics; thisclassification of antipsychotic medication was based largely on theactivating (neuroleptic) properties of the nervous system by thesedrugs. Subsequently, neuroleptic agents were shown to increase theconcentrations of dopamine metabolites in the brain suggesting alteredneuronal firing of the dopamine system. Additional evidence indicatedthat dopamine could increase the activity of adenylate cyclase in thecorpus striatum, an effect reversed by neuroleptic agents. Thus,cumulative evidence from these and later experiments strongly suggestedthat the neurotransmitter dopamine was involved in schizophrenia.

One of the major actions of antipsychotic medication is the blockade ofdopamine receptors in brain. Several dopamine systems appear to exist inthe brain and at least five classes of dopamine receptors appear tomediate the actions of this transmitter. These dopamine receptors differin their pharmacological specificity and were originally classified uponthese differences in the pharmacology of different chemical series.Butyrophenones, containing many potent antipsychotic drugs were quiteweak at the dopamine receptor that activated adenylate cyclase (nowknown as a D1 dopamine receptor). In contrast, they labelled otherdopamine receptors called D2 receptors) in the subnanomolar range and athird type D3 in the nanomolar range. Two additional receptor subtypeshave also been identified. D5 which is somewhat similar to D1 receptortype and D4 which is closely related to D3 and D2 receptor types.Phenothiazines possess nanomolar affinity for all three types ofdopamine receptors. Other drugs have been developed with greatspecificity for the D1 subtype receptor and for the D2 subtype receptor.

A certain group of drugs (such as sulpiride and clozapine) have beendeveloped with a lesser incidence of extrapyramidal side effects thanclassical neuroleptics. In addition, there is some indication that theymay be more beneficial in treating negative symptoms in some patients.Drugs of this class are often referred to as atypical antipsychoticagents. Since all D2 blockers do not possess a similar profile,hypotheses underlying the differences have been investigated. The majordifferences have been in the anticholinergic actions of the neurolepticsas well as the possibility that the dopamine receptors may differ inmotor areas from those in the limbic areas thought to mediate theantipsychotic responses. The existence of the D3, D4 and D5 and other asyet undiscovered dopamine receptors may contribute to this profile. Someof the atypical compounds possess similar activity at D2, D3 and D4receptors. The examples of this patent fall into this general class ofmolecules.

Using molecular biological techniques it has been possible to clonecDNAs coding for each of the pharmacologically defined receptors. Thereare at least two forms of D1-type receptors which have been classiifedas D1 and D5, and two forms of D2-type receptors, classified now as D2and D4 dopamine receptors. In addition, there is at least one form of D3dopamine receptor. Examples from the substituted aminomethylimidazoleseries of this patent possess differential affinities for each receptorsubtype.

Schizophrenia is characterized by a variety of cognitive dysfunctions;schizophrenic patients perform less well than other groups on mostcognitive or attentional tasks. The positive and negative symptomdimensions of schizophrenia are also associated with distinct cognitivedeficits. In general, positive symptoms (disordered thought processes,hallucinations and decisions) are related to auditory processingimairments including deficits in verbal memory and languagecomprehenion. Negative symptoms (social withdrawal and unresponsiveness)are related more to visual/motor dysfunctions including poorerperformance on visual memory, motor speed and dexterity tasks.

These disorders have an age of onset in adolescence or early adulthoodand persist for many years. The interaction of frontal andsepto-hippocampal brain systems, and failures of information processingand self monitoring have been theorized as the basis of positivesymptoms. Negative symptoms are thought to arise from abnormalities inthe interactions of frontal and striatal systems. Since cognitivedisturbances are present in most of the patients diagnosed as havingschizophrenia, it has been theorized that to understand the pathogenesisand etiology of schizophrenia one must understand the basic dysfunctionof the cognitive disorder.

The cognitive disturbances found in schizophrenia include, but are notlimited to, various verbal and visual memory deficits. Them are variousneurocognitive tasks for both animals and humans that have beendeveloped to assess memory deficits, as well as memory enhancements, ofvarious treatments. Many of the neurocognitive behavioral tasks aremodulated or mediated by eural activity within the hippocampal brainsystem noted above.

Drug substances that interact with the hippocampus are capable ofmodulating memory in animals. Certain memory paradigms employed inanimals have construct and predictive validity for memory assessment inhumans. In animals (rodents), paradigms such as the Step-Down PassiveAvoidance Task assay or the Spatial Water Maze Task assay reliablydetect deficits produced by certain drugs in humans. For example,commonly prescribed benzodiazepine anxiolytics and sedative hypnoticsare known to produce memory impairment in humans, including varyingdegrees of anterograde amnesia (depending on the exact drug). In thestep-down passive avoidance paradigm, these very same drugs disrupt thememory of animals given the compounds during the information acquisitionor processing period. Likewise, benzodiazepines disrupt informationprocessing and memories in the spatial water maze task in rodents. Thus,these animal models can be used to predict the memory impairing effectsof certain compounds in humans. Conversely, these same animal models canpredict the memory improving or enhancing effects of compounds inhumans. Although fewer in number, drugs that improve memory in humans(e.g., Nootroprice, Beta carbolines) produce memory enhancing effects inrats in these models. Therefore, the spatial water maze and step-downpassive avoidance paradigms in rodents are useful in predicting memoryimpairing and memory enhancing effects of test compounds in humans.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact withdopamine receptor subtypes.

The invention provides pharmaceutical compositions comprising compoundsof Formula I. The invention also provides compounds useful in treatingaffective disorders such as schizophrenia and depression as well ascertain movement disorders such as Parkinsonism. Furthermore compoundsof this invention may be useful in treating the extrapyramidyl sideeffects asssociated with the use of conventional neuroleptic agents.Since dopamine D3 and D4 receptor subtypes are particularly concentratedin the limbic system (Taubes, Science (1994) 265 1034) which controlscognition and emotion, compounds which interract with these receptorsmay have utility in the treatment of cognitive disorders. Such disordersmay be the cognitive deficits which are a significant component of thenegative symptoms (social withdrawal, and unresponsiveness) ofschizophrenia. Other disorders involving memory impairment or attentiondeficit disorders may also be treated with some of the compounds of thisinvention that interact specifically with dopamine D3 and/or D4 receptorsubtypes. Accordingly, the invention is directed to a compound ofFormula I: ##STR2## where R₁ is: aryl, heteroaryl, arylalkyl, cycloalkylor naphthyl; unsubstituted or substituted by up to 3 substituents whichmay be the same or different and represent hydrogen, halogen,trifluoromethyl, cyano, straight or branched chain lower alkyl having1-6 carbon atoms, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6carbon atoms, or SO₂ R₉ where R₉ is NH₂ or NHCH₃ ;

X is: N or NR₂ where R₂ is hydrogen or straight or branched chain loweralkyl having 1-6 carbon atoms.

Y is: N or CR₃

Z is: CR₃ or N

provided that Y and Z are not both CR₃ ; and

provided that Y and Z are not both N;

R₃ is: hydrogen, lower alkyl, halogen, hydroxy lower alkyl or phenylunsubstituted or substituted by up to three substituents which may bethe same or different and represent hydrogen, halogen, trifluoromethyl,cyano, sulfonamido, hydroxy, straight or branched chain lower alkylhaving 1-6 carbon atoms, or straight or branched chain lower alkoxyhaving 1-6 carbon atoms;

R₄ is: hydrogen or straight or branched chain lower alkyl having 1-6carbon atoms, or R₃ and R₄ together may represent --(CH₂)_(n).sbsb.1 --where n₁ is 2, 3 or 4; or R₂ and R₄ together may represent--(CH₂)_(n).sbsb.2 -- where n₂ is 2, 3 or 4.

m is: zero, one or two

R₅ and R₆ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, aryl, straight orbranched chain lower alkyl having 1-6 carbon atoms or R₂ and R₅ togethermay represent --(CH₂)_(n).sbsb.3 -- where n₃ is 2 or 3; or

NR₅ R₆ together represent: 2-(1,2,3,4-tetrahydroisoquinolinyl), eitherunsubstituted or mono or disubstituted with halogen, hydroxy, straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; or

NR₅ R₆ represents: ##STR3## where R₇ is phenyl, benzyl or phenethyl withthe phenyl ring unsubstituted or substituted with up to threesubstituents which may be the same or different and represent hydrogen,halogen, trifluoromethyl, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms; or

NR₅ R₆ represents: ##STR4## where p is 1, 2, or 3;

W is N or CH; and

W is N and R₈ is hydrogen, phenyl, pyridyl or pyrimidinyl, unsubstitutedor mono or disubstituted with halogen, hydroxy, straight or branchedchain lower alkyl having 1-6 carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms; or

W is CH and R₈ is optionally substituted phenyl or an arylalkyl groupsuch as, for example, phenylalkyl where the phenyl ring may besubstituted with up to three substituents independently selected fromhydrogen, halogen, trifluoromethyl, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms.

These compounds are highly selective partial agonists or antagonists atbrain dopamine receptor subtypes or prodrugs thereof and are useful inthe diagnosis and treatment of affective disorders such as schizophreniaand depression as well as certain movement disorders such asParkinsonism. Furthermore, compounds of this invention may be useful intreating the extrapyramidyl side effects associated with the use ofconventional neuroleptic agents. Furthermore, compounds of thisinvention may have utility in the treatment of cognitive disorders. Suchdisorders may be the cognitive deficits which are a significantcomponent of the negative symptoms (social withdrawal, andunresponsiveness) of schizophrenia or other disorders involving memoryimpairment or attention deficit disorders.

The compounds of the invention, such as, for example, 2-Phenyl-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole dihydrochloride(compound 23), 2-Phenyl-4(5)-(4-(2-pyridyl)-piperazin-1-yl)-methyl!-imidazole dihydrochloride(Compound 24), and 2-Phenyl-4(5)-(4-phenyl-piperazin-1-yl)-methyl!-imidazole dihydrochloride (Compound45), are antagonists binding to dopamine D4 receptors in both the ratand human hippocampus.

As noted above, the hippocampus is associated with both schizophrenia,and general memory processes in humans. In rodents, compound 23 producesmemory enhancing effects in both the step-down passive avoidance assayas well as in the spatial water maze assay. Without being bound by aparticular theory, it is believed that the D₄ receptors located in thehippocampus mediate the memory enhancing effects of the compounds of theinvention. Therefore, since (1) compound 23 is active in animal modelsthat are predictive of cognition enhancement, and specificallyenhancement of memory and learning, and (2) compound 23 binds to D4receptors in the hippocampus, the D₄ class of dopamine antagonists,including the compounds of the invention, are useful for enhancingmemory in humans.

Thus, the invention further provides methods for enhancing cognition,and specifically learning and memory, in mammals. These methods compriseadministering to a mammal such as a human a compound of the invention inan amount effective to enhance cognition.

BRIEF DESCRIPTION OF THE DRAWING

FIGS. 1, 2, and 3 show representative substituted aminomethylimidazolesof the present invention.

DETAILED DESCRIPTION OF THE INVENTION

In addition to compounds of general formula I described above, thepresent invention further encompasses compounds of Formula II: ##STR5##where R₁, X, Y, Z, m are as defined above for Formula I;

R₃ is hydrogen, halogen, straight or branched chain lower alkyl having1-6 carbon atoms;

R₄ is hydrogen or straight or branched chain lower alkyl having 1-6carbon atoms, or, where Z is CR₃, R₃ and R₄ together may represent--(CH₂)_(n).sbsb.1 -- where n 1 is 2, 3 or 4; or R₂ and R₄ together mayrepresent --(CH₂)_(n).sbsb.2 -- where n2 is 2, 3 or 4.

R₂ and R₅ together may represent --(CH₂)_(n).sbsb.3 -- where n3 is 2 or3;

R₆ is hydrogen, straight or branched chain lower alkyl, phenyl orarylalkyl; or

NR₅ R₆ represents: ##STR6## where R₇ is as defined for Formula I.

NR₅ R₆ represents: ##STR7## where p, and is 1, 2, or 3;

W is N and R₈ is phenyl, pyridyl or pyrimidinyl, unsubstituted or monoor disubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms; or

W is CH and R₈ is optionally substituted phenyl or an arylalkyl groupsuch as, for example, phenylalkyl where the phenyl ring may besubstituted with up to three substituents independently selected fromhydrogen, halogen, trifluoromethyl, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms.

Preferred compounds according to Formula I include those where Z is CR₃and R₃ and R₄ together form a 25 or 6-membered ring; R₁ is substitutedor unsubstituted phenyl; X is: N; Y is: N; and R₅ and R₆ represents:##STR8## where p is 2; and

W is N and R₈ is phenyl, pyridyl or pyrimidinyl, unsubstituted or monoor disubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms; or

W is CH and R₈ is optionally substituted phenyl or an arylalkyl groupsuch as, for example, phenylalkyl where the phenyl ring may besubstituted with up to three substituents independently selected fromhydrogen, halogen, trifluoromethyl, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms.

Preferred compounds according to Formula II are those where R₁ is phenyloptionally substituted in the 4-position with halogen or alkyl, Y and Xare nitrogen, Z is CH, R₄ is hydrogen, m is 0, and NR₄ R₅ represents4-substituted piperazin-1-yl or 4-substituted piperidin-1-yl. Thepiperazinyl or piperidinyl groups are substituted in the 4-position withpyridyl or pyrimidinyl, or phenyl or benzyl each of which is optionallysubstituted, preferably in the 4-position, with halogen, alkyl, oralkoxy. The preferred piperidinyl groups are optionally substituted inthe 3-position with alkyl, and more preferably, methyl, groups.Particularly preferred R₁ groups are 4-methylphenyl and 4-halophenylgroups.

The present invention also encompasses compounds of Formula IIA:##STR9## where R₁ is: aryl, heteroaryl, arylalkyl, cycloalkyl ornaphthyl; unsubstituted or substituted by up to 3 substituents which maybe the same or different and represent hydrogen, halogen,trifluoromethyl, cyano, straight or branched chain lower alkyl having1-6 carbon atoms, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6carbon atoms, or SO₂ R₉ where R₉ is NH₂ or NHCH₃ ;

R₂ is hydrogen or alkyl;

R₃ is: hydrogen, lower alkyl, halogen, hydroxy lower alkyl, or phenylunsubstituted or substituted by up to three substituents independentlyselected from hydrogen, halogen, trifluoromethyl, cyano, sulfonamido,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms;

R₄ is: hydrogen or straight or branched chain lower alkyl having 1-6carbon atoms, or R₃ and R₄ together may represent --(CH₂)_(n).sbsb.1 --where n 1 is 2, 3 or 4; or R₂ and R₄ together may represent--(CH₂)_(n).sbsb.2 -- where n₂ is 2, 3 or 4.

m is: zero, one or two

R₅ and R₆ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, aryl, straight orbranched chain lower alkyl having 1-6 carbon atoms or R₂ and R₅ togethermay represent --(CH₂)_(n).sbsb.3 -- where n3 is 2 or 3; or

NR₅ R₆ together represent: 2-(1,2,3,4-tetrahydroisoquinolinyl), eitherunsubstituted or mono or disubstituted with halogen, hydroxy, straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; or

NR₅ R₆ represents: ##STR10## where R₇ is phenyl, benzyl or phenethylwith the phenyl ring unsubstituted or substituted with up to threesubstituents which may be the same or different and represent hydrogen,halogen, trifluoromethyl, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms; or

NR₅ R₆ represents: ##STR11## where p is 1, 2, or 3; and

W is N and R₈ is hydrogen, phenyl, pyridyl or pyrimidinyl, unsubstitutedor mono or disubstituted with halogen, hydroxy, straight or branchedchain lower alkyl having 1-6 carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms; or

W is CH and R₈ is optionally substituted phenyl, optionally substitutedbenzoyl, or an arylalkyl group such as, for example, phenylalkyl wherethe phenyl ring may be substituted with up to three substituentsindependently selected from hydrogen, halogen, trifluoromethyl, hydroxy,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms.

Preferred compounds of Formula IIA and those where R₁ is optionallysubstituted phenyl; R₂ and R₄ are hydrogen; and R₅ is alkyl and R₆ isarylalkyl, preferably optionally substituted, and more preferablyunsubstituted, benzyl; or NR₅ R₆ is: ##STR12## where p, W, and R₈ are asdefined above for Formula I.

Particularly preferred compounds of Formula IIA arc those where R₁ isoptionally substituted phenyl; R₂ and R₄ arc hydrogen; R₅ is alkyl andR₆ is arylalkyl, preferably optionally substituted, and more preferablyunsubstituted, benzyl; or NR₅ R₆ is: ##STR13## where p, is 2;

W is N and R₈ is phenyl, pyridyl or pyrimidinyl, unsubstituted or monoor disubstituted with halogen, or straight or branched chain loweralkoxy having 1-6 carbon atoms.

Particularly preferred compounds of Formula IIA are those where R₁ isoptionally substituted phenyl; R₂ and R₄ are hydrogen; R₃ is hydrogen;R₅ is alkyl and R₆ is arylalkyl, preferably optionally substituted, andmore preferably unsubstituted, benzyl; or NR₅ R₆ is: ##STR14## where p,is 2;

W is N and R₈ is phenyl, pyridyl or pyrimidinyl, unsubstituted or monoor disubstituted with halogen, or straight or branched chain loweralkoxy having 1-6 carbon atoms.

Other particularly preferred compounds of Formula IIA are those where R₁is phenyl; R₂ and R₄ are hydrogen; R₃ is hydrogen; and NR₅ R₆ is:##STR15## where p, is 2; and

W is CH and R₈ is optionally halogenated or alkoxylated phenyl or anarylalkyl group such as, for example, phenylalkyl where the phenyl ringis optionally substituted with up to three substituents independentlyselected from hydrogen, halogen, or straight or branched chain loweralkoxy having 1-6 carbon atoms.

The present invention also encompasses compounds of Formula III:##STR16## where R₁ is aryl, heteroaryl, or naphthyl; unsubstituted orsubstituted by up to three substituents which may be the same ordifferent and represent hydrogen, halogen, trifluoromethyl, cyano,straight or branched chain lower alkyl having 1-6 carbon atoms, hydroxy,straight or branched chain lower alkyl having 1-6 carbon atoms, straightor branched chain lower alkoxy having 1-6 carbon atoms, or SO₂ R₉ whereR₉ is NH₂ or NHCH₃ ;

X, Y, Z, m, are as defined above for Formula I;

R₃ is hydrogen, halogen, straight or branched chain lower alkyl having1-6 carbon atoms;

R₄ is hydrogen or straight or branched chain lower alkyl having 1-6carbon atoms, or when Z is CR₃, R₃ and R₄ together may represent--(CH₂)_(n).sbsb.1 -- where n₁ is 2, 3 or 4;

NR₅ R₆ represents: ##STR17## where R₇ is as defined above for Formula I;or

NR₅ R₆ represents: ##STR18## where p, and is 1, 2, or 3;

W is N and R₈ is phenyl, pyridyl or pyrimidinyl, unsubstituted or monoor disubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms; or

W is CH and R₈ is optionally substituted phenyl or an arylalkyl groupsuch as, for example, phenylalkyl where the phenyl ring may besubstituted with up to three substituents independently selected fromhydrogen, halogen, trifluoromethyl, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms.

In addition, the present invention encompasses compounds of Formula IV:##STR19## where R₁ is phenyl or naphthyl, each of which may besubstituted by up to three substituents independently selected fromhydrogen, halogen, trifluoromethyl, cyano, straight or branched chainlower alkyl having 1-6 carbon atoms, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atom, straight or branched chain loweralkoxy having 1-6 carbon atom, or SO₂ R₉ where R₉ is NH2 or NHCH₃.

X, Y, Z, are as defined above for Formula I,

R₃ is hydrogen, halogen, straight or branched chain lower alkyl having1-6 carbon atoms;

R₄ is hydrogen or straight or branched chain lower alkyl having 1-6carbon atoms;

m is zero;

NR₅ R₆ represents: ##STR20## where R₇ is as defined above for Formula I;or

NR₅ R₆ represents: ##STR21## where p, and is 1, 2, or 3;

W is N and R₈ is phenyl, pyridyl or pyrimidinyl, unsubstituted or monoor disubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms; or

W is CH and R₈ is optionally substituted phenyl or an arylalkyl groupsuch as, for example, phenylalkyl where the phenyl ring may besubstituted with up to three substituents independently selected fromhydrogen, halogen, trifluoromethyl, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms.

The invention timber encompasses compounds of Formula V: ##STR22## andthe pharmaceutically acceptable non-toxic salts thereof wherein R₁ and Tare the same or different and represent hydrogen, halogen, hydroxy,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms;

M is ##STR23## where R₂ is hydrogen or straight or branched chain loweralkyl having 1-6 carbon atoms, or R₁ and R₂ together may represent--(CH₂)_(n).sbsb.1 where n₁ is 1, 2, or 3;

X and Z are the same or different and represent hydrogen, halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,straight or branched chain lower alkoxy having 1-6 carbon atoms or SO₂R₆ where R₆ is straight or branched chain lower alkyl having 1-6 carbonatoms;

Y is hydrogen, halogen, amino, or straight or branched chain lower alkylhaving 1-6 carbon atoms;

R₃ is hydrogen or straight or branched chain lower alkyl having 1-6carbon atoms, or R₃ and R₄ together may represent --(CH₂)_(n).sbsb.2 --where n2 is 3 or 4; and

R₄ and R₅ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl orpyridylalkyl where each alkyl is straight or branched chain alkyl having1-6 carbon atoms; or

R₂ and R₅ together may represent --(CH₂)_(n).sbsb.3 -- where n₃ is 2 or3; or

NR₄ R₅ represents 2-(1,2,3,4-tetrahydroisoquinolinyl), or2-(1,2,3,4-tetrahydroiso-quinolinyl) mono or disubstituted with halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; or##STR24## where W is N or CH; and

R₇ is hydrogen, phenyl, pyridyl or pyrimidinyl, or phenyl, pyridyl orpyrimidinyl, each of which is mono or disubstituted with halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

W-R₇ is oxygen or sulfur; and

n is 1, 2, or 3.

The present invention further encompasses compounds of Formula VI:##STR25## wherein R₁ is hydrogen, halogen, hydroxy, straight or branchedchain lower alkyl having 1-6 carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atom;

M is ##STR26## where R₂ is hydrogen or, straight or branched chain loweralkyl having 1-6 carbon atoms, or R₁ and R₂ together may represent--(CH₂)_(n).sbsb.1 where n₁ is 1, 2, or 3;

X is hydrogen, halogen, hydroxy, straight or branched chain lower alkylhaving 1-6 carbon atoms, straight or branched chain lower alkoxy having1-6 carbon atoms or SO₂ R₆ where 1-6 is straight or branched chain loweralkyl having 1-6 carbon atoms;

R₃ is hydrogen or straight or branched chain lower alkyl having 1-6carbon atoms; or R₃ and R₄ together may represent --(CH₂)_(n).sbsb.2 --where n₂ is 3 or 4; and

R₄ and R₅ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, phenylalkyl orpyridylalkyl where each alkyl is straight or branched chain lower alkylhaving 1-6 carbon atoms; or

R₂ and R₅ together may represent --(CH₂)_(n).sbsb.3 -- where n₃ is 2 or3; or

NR₄ R₅ represents 2-(1,2,3,4-tetrahydroisoquinolinyl) or2-(1,2,3,4-tetrahydroisoquinolinyl) mono or disubstituted with halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; or##STR27## where W is N or CH;

R₇ is hydrogen, phenyl, pyridyl or pyrimidinyl, or phenyl, pyridyl orpyrimidinyl, each of which may be mono or disubstituted with halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

W-R₇ is oxygen or sulfur; and

n is 1, 2, or3.

The present invention also encompases compounds of Formula VII:##STR28## wherein R₁ is hydrogen, halogen, hydroxy, straight or branchedchain lower alkyl having 1-6 carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms;

M is ##STR29## where R₂ is hydrogen, or straight or branched chain loweralkyl having 1-6 carbon atoms, or R₁ and R₂ together may represent--(CH₂)_(n).sbsb.1 where n₁ is 1, 2, or 3;

R₃ is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms, or R₃ and R₄ together may represent --(CH₂)_(n).sbsb.2 --where n₂ is 3 or 4; or

R₄ and R₅ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, aryl straight orbranched chain lower alkyl having 1-6 carbon atoms or R₂ and R₅ togethermay represent --(CH₂)_(n).sbsb.3 -- where n₃ is 2 or 3; or

NR₄ R₅ represents 2-(1,2,3,4-tetrahydroisoquinolinyl), or2-(1,2,3,4-tetrahydroiso-quinolinyl) mono or disubstituted with halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; or##STR30## where W is N or CH;

R₇ is

hydrogen, phenyl, pyridyl or pyrimidinyl; or

phenyl, pyridyl or pyrimidinyl mono or disubstituted with halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

W-R₇ is oxygen or sulfur; and

n is 1, 2, or 3.

In addition, the present invention encompasses compounds of FormulaVIII: ##STR31## wherein M is ##STR32## where R₂ is hydrogen or, straightor branched chain lower alkyl having 1-6 carbon atoms, or R₁ and R₂together may represent --(CH₂)_(n).sbsb.1 where n₁ is 1, 2, or 3;

X is hydrogen, halogen, hydroxy, straight or branched chain lower alkylhaving 1-6 carbon atoms, straight or branched chain lower alkoxy having1-6 carbon atoms, or SO₂ R₆ where R₆ is straight or branched chain loweralkyl having 1-6 carbon atoms;

R₃ is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms, or R₃ and R₄ together may represent --(CH₂)_(n).sbsb.2 --where n2 is 3 or 4; and

R₄ and R₅ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, phenylalkyl orpyridylalkyl where each alkyl is straight or branched chain lower alkylhaving 1-6 carbon atoms; or

R₂ and R₅ together may represent --(CH₂)_(n).sbsb.3 -- where n3 is 2 or3; or

NR₄ R₅ represents 2-(1,2,3,4-tetrahydroisoquinolinyl), or2-(1,2,3,4-tetrahydroiso-quinolinyl) mono or disubstituted with halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; or##STR33## where W is N or CH;

R₇ is hydrogen, phenyl, pyridyl or pyrimidinyl, or hydrogen, phenyl,pyridyl or pyrimidinyl, mono or disubstituted with halogen, hydroxy,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms; or

W-R₇ is oxygen or sulfur; and

n is 1, 2, or 3.

The invention also provides compounds of Formula IX: ##STR34## where Xrepresents a hydrogen or halogen;

R_(a) and R_(b) are the same or different and represent hydrogen oralkoxy; and

NR₄ R₅ represents 4-(substituted or unsubstituted phenyl)piperazin-1-ylor 4-phenyl-piperidin-1-yl, where the phenyl group may be substitutedwith hydrogen, alkyl, or alkoxy.

The invention also provides compounds of Formula X: ##STR35## where Xrepresents a hydrogen or halogen;

R represents hydrogen or alkyl;

R_(a) and R_(b) are the same or different and represent hydrogen oralkoxy; and

A and B are the same or different and represnt hydrogen or(4-(2-pyrimidinyl)piperazin-1-yl)methyl.

Preferred compounds of Formula X are those where R is hydrogen or methyland X, R_(a) and R_(b) are hydrogen. Particularly preferred compounds ofFormula X are those where R is hydrogen or methyl, X, R_(a) and R_(b)are hydrogen, and A and B are different and represent hydrogen or(4-(2-pyrimidinyl)piperazin-1-yl)methyl.

Also within the scope of the invention are compounds of Formula XI:##STR36## where X represents a hydrogen or halogen;

R represents hydrogen or alkyl;

R_(a) and R_(b) are the same or different and represent hydrogen oralkoxy; and

R_(c) is a group of the formula: ##STR37## where W is N or CH;

R represnts alkyl;

R_(d) represents pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy; and

R_(e) is alkyl.

Preferred compounds of Formula XI are those where X, R_(a), R_(b), andR_(e) are hydrogen and R_(c) is a 4-substituted piperazin-1-yl orpiperidin-1-yl group. Particularly preferred compounds of Formula XI arethose where the 4-substituted piperazin-1-yl or piperidin-1-yl groupsare substituted with optionally substituted phenyl, phenylalkyl,2-pyridyl or 2-pyrimidinyl groups. Other preferred compounds of formulaXI are those where X, R_(a), R_(b), and R_(e) are hydrogen, R_(e) ismethyl and R_(c) is piperazin-1-yl or piperidin-1-yl each of which issubstituted in the 4-position with benzyl, pyridyl or pyrimidinyl.

The invention also provides compounds of Formula XII: ##STR38## where Wis N or CH;

R_(f) is halogen or alkyl;

R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy.

Preferred compounds of Formula XII are those where R_(f) is halogen ormethyl, W is nitrogen, and R_(d) is pyridyl, pyrimidinyl, or benzyl.Particularly preferred compounds of Formula XII are those where R_(f) ishalogen or methyl, W is nitrogen, and R_(d) is pyrimidinyl.

The invention further provides compounds of Formula XIII: ##STR39##where W is N or CH;

R_(f) is alkyl; and

R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy.

Preferred compounds of Formula XIII are those where R_(f) is methyl, Wis nitrogen, and R_(d) is pyridyl, pyrimidinyl, or benzyl. Particularlypreferred compounds of Formula XIII are those where R_(f) is methyl, Wis nitrogen, and R_(d) is pyrimidinyl.

The invention further provides compounds of Formula XIV: ##STR40## whereAr is 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-pyrazinyl, 2-thienyl, or2-quinolinyl,

W is N or CH;

R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy.

Preferred compounds of Formula XIV are those where W is CH, and R_(d) ispyridyl, pyrimidinyl, or benzyl.

The invention further provides compounds of Formula XV: ##STR41## whereAr is 1- or 2-naphthyl, phenyl or phenyl mono-, di- or trisubstitutedwith alkyl, alkoxy or halogen,

W is N or CH;

R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy.

Preferred compounds of Formula XV are those where Ar is phenyl, W is CH,and R_(d) is pyridyl, pyrimidinyl, or benzyl.

The invention further provides compounds of Formula XVI: ##STR42## whereX represents a hydrogen or halogen;

R_(a) and R_(b) are the same or different and represent hydrogen oralkoxy;

W is N or CH;

R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, hydroxy, alkyl or alkoxy.

Preferred compounds of Formula XVI are those where X, R_(a) and R_(b)are hydrogen, W is CH, and R_(d) is pyridyl, pyrimidinyl, or benzyl.

The invention further provides compounds of Formula XVII: ##STR43##where X represents a hydrogen or halogen;

R_(a) and R_(b) are the same or different and represent hydrogen oralkoxy;

W is N or CH;

R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, hydroxy, alkyl or alkoxy.

Preferred compounds of Formula XVII are those where X, R_(a) and R_(b)are hydrogen, W is N, and R_(d) is pyridyl, pyrimidinyl, or benzyl.

The invention further provides compounds of Formula XVIII: ##STR44##where m is 0, 1 or 2;

X represents a hydrogen or halogen;

R_(a) and R_(b) are the same or different and represent hydrogen oralkoxy;

W is N or CH;

R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, hydroxy, alkyl or alkoxy.

Preferred compounds of Formula XVIII are those where X, R_(a) and R_(b)are hydrogen, W is N, and R_(d) is pyridyl, pyrimidinyl, or benzyl.

The invention further provides compounds of Formula XIX: ##STR45## wherem is 0, 1 or 2;

X represents a hydrogen or halogen;

R_(a) and R_(b) are the same or different and represent hydrogen oralkoxy;

W is N or CH;

R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, hydroxy, alkyl or alkoxy.

Preferred compounds of Formula XIX are those where X, R_(a) and R_(b)are hydrogen, W is N, and R_(d) is pyridyl, pyrimidinyl, or benzyl.Other preferred compounds of formula XIX are those where X, R_(a) andR_(b) are hydrogen, W is CH, and R_(d) is phenyl substituted withhalogen and/or hydroxy.

The invention also provides compounds of Formula XX: ##STR46## whereR_(a) is alkyl;

W is N or CH;

R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy.

Preferred compounds of Formula XX are those where W is nitrogen, R_(a)is hydrogen or methyl, and R_(d) is pyridyl, pyrimidinyl, or benzyl.Other preferred compounds according to Formula XX are those where W isCH, R_(a) is hydrogen or methyl, and R_(d) is pyridyl, pyrimidinyl, orbenzyl.

The invention also provides compounds of Formula XXI: ##STR47## where Wis N or CH; and

R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy.

Preferred compounds of Formula XXI are those where W is nitrogen, R_(a)is hydrogen or methyl, and R_(d) is pyridyl, pyrimidinyl, or benzyl.Other preferred compounds according to Formula XXI are those where W isCH, R_(a) is hydrogen or methyl, and R_(d) is pyridyl, pyrimidinyl, orbenzyl.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in FIG. 1and their pharmaceutically acceptable salts. Non-toxic pharmaceuticallyacceptable salts include salts of acids such as hydrochloric,phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluene sulfonic,hydroiodic, acetic and the like. Those skilled in the art will recognizea wide variety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the an will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

By "aryl" and "Ar" is meant an aromatic carbocyclic group having asingle ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiplecondensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), whichcan optionally be unsubstituted or substituted with e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy.

By "alkyl" and "lower alkyl" is meant straight and branched chain alkylgroups having from 1-6 carbon atoms.

By "lower alkoxy" and "alkoxy" is meant straight and branched chainalkoxy groups having from 1-6 carbon atoms.

By "hydroxy lower alkyl" or "hydroxy alkyl" is meant an alkyl groupsubstituted by at least one hydroxy group. Preferred hydroxy alkylgroups are straight chain alkyl groups substituted with one hydroxygroup at the terminal carbon atom.

By "heteroaryl" is meant 5, 6, or 7 membered aromatic ring systemshaving at least one hetero atom selected from the group consisting ofnitrogen, oxygen and sulfur. Examples of heteroaryl groups are pyridyl,pyrimidinyl, pyrrolo, pyrazolo, pyrazinyl, pyridazinyl, oxazolo,furanyl, quinoline, isoquinoline, thiazole, and thienyl, which canoptionally be unsubstituted or substituted with e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy.

By "halogen" is meant fluorine, chlorine, bromine and iodine.

By "arylalkyl" is meant the group --R--Ar where Ar is an aryl group andR is a straight or branched chain aliphatic group. Arylalkyl groups mayoptionally be substituted with, e.g., halogen, lower alkyl, loweralkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, and hydroxy.Preferred arylalkyl groups in the above formulas where W is CH and R₈represents arylalkyl are phenylalkyl groups where the alkyl portion islower alkyl. A particularly preferred phenylalkyl group is benzyl wherethe phenyl ring may be substituted with up to three substituentsindependently selected from hydrogen, halogen, trifluoromethyl, hydroxy,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms.

By "cycloalkyl" is meant cyclic hydrocarbons having from 3-8 carbonatoms. These cyclic hydrocarbon groups may be substituted with up tothree substituents independently selected from hydrogen, halogen,trifluoromethyl, cyano, straight or branched chain lower alkyl having1-6 carbon atoms, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6carbon atoms, or SO₂ R₉ where R₉ is NH₂ or NHCH₃.

The pharmaceutical utility of compounds of this invention are indicatedby the following assays for dopamine receptor subtype affinity.

Assay for D2 and D3 receptor binding activity

Striatial tissue is dissected from adult male Sprague Dawley rats or BHK293 cells are harvested containing recombinantly produced D2 or D3receptors. The sample is homogenized in 100 volumes (w/vol) of 0.05MTris HCl buffer at 4° C. and pH 7.4. The sample is then centrifuged at30,000×g and resuspended and rehomogenized. The sample is thencentrifuged as described and the final tissue sample is frozen untiluse. The tissue is resuspended 1:20 (wt/vol) in 0.05M Tris HCl buffercontaining 100 mM NaCl.

Incubations are carried out at 48° C. and contain 0.5 ml of tissuesample, 0.5 nM ³ H-raclopride and the compound of interest in a totalincubation volume of 1.0 ml. Nonspecific binding is defined as thatbinding found in the presence of 10⁻⁴ M dopamine; without furtheradditions, nonspecific binding is less than 20% of total binding. Thebinding characteristics of examples of this patent are shown in Table 1for rat striatal homogenates.

                  TABLE I                                                         ______________________________________                                        Compound Number.sup.1                                                                          IC.sub.50 (mM)                                               ______________________________________                                         1               0.900                                                         8               0.011                                                        16               0.014                                                        19               0.100                                                        21               0.018                                                        24               0.620                                                        26               0.200                                                        ______________________________________                                         .sup.1 Compound numbers relate to compounds described in the examples         below and/or shown in the figures.                                       

Assay for D4 receptor binding activity

Clonal cell lines expressing the human dopamine D4 receptor subtype wereharvested in PBS and the cells centrifuged and the pellets stored at-80° C. until used in the binding assay. The pellets were resuspendedand the cells lysed at 4° C. in 50 mM Tris pH 7.4 buffer containing 120mM NaCl, 1 mM EDTA and 5 mM MgCl₂. The homogenate is centrifuged at48000×g for 10 minutes at 4° C. The resulting pellet is resuspended infresh buffer and centrifuged again. After resuspension of the pellet infresh buffer at 100 ml aliquot is removed for protein determination. Theremaining homogenate is centrifuged as above, the supernatant moved andthe pellet stored at 4° C. until needed at which time it is resuspendedto a final concentration of 625 mg/ml (250 mg per sample) with 50 mMTris buffer (pH 7.4) and 120 mM NaCl just prior to use. Incubations werecarried out for 60 minutes at 25° C. in the presence of 0.1 nM ³ H!YM-09151-2. The incubation was terminated by rapid filtration throughWhatman GF/C filters and rinsed with 2×4 ml washes of chilled 50 mM Tris(pH 7.4) and 120 mM NaCl. Non-specific binding was determined with 1 mMspiperone and radioactivity determined by coiunting in an LKB betacounter. Binding parameters were determined by non-linear least squaresregression analysis, from which the inhibition constant (Ki) could becalculated for each test compound. The binding characteristics of someexamples of this patent are shown in Table 2 for the dopamine D4 bindingassay. In general, compounds of the accompanying examples were tested inthe above assay, and all were found to possess a Ki value for thedisplacement of 3H!YM-09151-2 from the human dopamine D4 receptorsubtype of below 500 nM. Some specific data is indicated in Table 2.

                  TABLE 2                                                         ______________________________________                                        Compound Number.sup.1                                                                          Ki (mM)                                                      ______________________________________                                        19               0.001                                                        20               0.014                                                        22               0.048                                                        23               0.003                                                        24               0.001                                                        25               0.002                                                        43               0.014                                                        45               0.005                                                        47               0.053                                                        50               0.005                                                        52               0.002                                                        55               0.500                                                        56               0.450                                                        58               0.003                                                        60               0.015                                                        61               0.013                                                        65               0.013                                                        ______________________________________                                         .sup.1 Compound numbers relate to compounds described in the examples         below and/or shown in the figures.                                       

Compounds 8, 16, 19, 21, 23, 24, 25 and 52 are particularly preferredembodiments of the present invention because of their potency in bindingto dopamine receptor subtypes.

The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the an for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known an using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono-or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of the aboveindicated conditions (about 0.5 mg to about 7 g per patient per day).The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Dosage unitforms will generally contain between from about 1 mg to about 500 mg ofan active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and ram of excretion, drug combination and the severityof the particular disease undergoing therapy.

An illustration of the preparation of representative2-phenyl-4-aminomethyl-imidazoles of the present invention is shown inScheme I. Those having skill in the art will recognize that the startingmaterials may be varied and additional steps employed to producecompounds encompassed by the present invention. ##STR48## where S₁, S₂,S₃, S₄, and S₅ are the same or different and represent hydrogen,halogen, trifluoromethyl, cyano, straight or branched chain lower alkylhaving 1-6 carbon atoms, hydroxy, straight or branched chain lower alkylhaving 1-6 carbon atoms, straight or branched chain lower alkoxy having1-6 carbon atoms, or SO₂ R₉ where R₉ is NH₂ or NHCH₃ ;

R₅ and R₆ are as defined as above for Formula I; or

NR₅ R₆ together represent cyclic groups as defined above for Fromula I.

Alternatively, compounds of the invention may be prepared according tothe reactions shown in Scheme 2. ##STR49## where R₁, T, M, X, Y, Z, R₄,and R₅ are as defined for Formula V above.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures and compounds described in them.

EXAMPLE I ##STR50##

A mixture of 6.45 g 5-bromo-o-anisaldehyde, 2.2 g of hydroxylaminehydrochloride, 4.1 g of sodium formate and 20 mL formic acid were heatedat 100° C. with stirring for 1 h. The reaction mixture was poured ontoice water and the mixture was made basic by the careful addition of 50%sodium hydroxide. The product was extracted with ether, the etherextracts were dried over magnesium sulfate and the solvent was removedin vacuo. The residue was crystallized from ether/hexane to afford5-bromo-2-methoxybenzonitrile.

EXAMPLE II ##STR51##

A mixture of 4.0 g 5-bromo-2-methoxybenzonitrile, 5 g 3 A molecularsieves and 60 mL of anhydrous methanol was saturated with HCl gas at 0°C. and allowed to stand at 0° C. for 24 h. The solvent was removed invacuo and the residue taken up in 75 mL of anhydrous methanol andsaturated with ammonia gas at room temperature. The reaction mixture wasthen heated at 80° C. for 4 h in a sealed tube. The sovent was removedin vacuo, the reaction mixture was diluted with 3N HCl and washed withethyl acetate to remove unreacted nitrile. The aqueous layer was madebasic with 50% NaOH and the product was extracted three times with 10%methanol in methylene chloride. The combined organic extracts were driedover potassium carbonate and the solvents removed in vacuo to afford5-bromo-2-methoxybenzamidine as a glassy solid.

EXAMPLE III ##STR52##

To a solution of 20 g 1,1,1,3,3,3-hexamethyldisilazane in 150 mL dryether was added 5 mL 2.4M n-butyllithium in hexane. After 10 min at roomtemperature, 16.3 g 2,3-dimethoxybenzonitrile was added in one portionand the mixture was kept at room temperature for 16 h. The reactionmixture was then poured onto excess 3N HCl. The aqueous layer wasseparated, basified with 50% NaOH and the product was extracted threetimes with 10% methanol in methylene chloride. The combined organicextracts were dried over potassium carbonate and the solvents removed invacuo to afford 2,3-dimethoxybenzamidine as a glassy solid.

EXAMPLE IV ##STR53##

A mixture of 1.5 g of 5-bromo-2-methoxybenzamidine, 1.0 g of1,3-dihydroxyacetone dimer, 1.3 g of ammonium chloride, 3 mL oftetrahydrofuran and 10 mL concentrated aqueous ammonium hydroxide washeated at 90° C. for 3 h. The reaction mixture was chilled on ice andthe precipitated product was collected and recrystallized from methanolto afford 2-(5-bromo-2-methoxyphenyl)-4-hydroxymethylimidazole as ayellow solid.

EXAMPLE V ##STR54##

A mixture of 500 mg 2-(5-bromo-2-methoxyphenyl)-4-hydroxymethylimidazoleand 1.5 mL thionyl chloride was heated at 80° C. for 15 min and thenconcentrated under reduced pressure. Diethyl ether (15 mL) was added andthe resulting solid was collected and washed with ether. This solid wasadded in one portion to a mixture of 3 mL of dimethylamine, 15 mLisopropanol and 30 mL of methylene chloride and the mixture was stirredfor 20 min. The solvents were removed in vacuo and the residue wasdissolved in 2N HCl and washed two times with ethyl acetate. The aqueouslayer was made basic with 50% NaOH and the product was extracted withmethylene chloride. The organic extracts were dried over magnesiumsulfate, the solvents removed in vacuo, and the residue was treated withethanolic HCl/ether to afford 2-(5-bromo-2-methoxyphenyl)-4(5)-(N,N-dimethyl)aminomethyl!-imidazote dihydrochloride (Compound 1), m.p.242°-243° C.

EXAMPLE VI

The following compounds were prepared essentially according to theprocedure described in Examples I-V:

(a) 2-Phenyl-4(5)- (N,N-dimethyl)aminomethyl!-imidazole dihydrochloride(Compound 2), m.p. 259°-260° C.

(b) 2-Phenyl-4(5)-(piperidinomethyl)-imidazole dihydrochloride (Compound3), m.p. 245°-247° C.

(c) 2-Phenyl-4(5)- (N-methyl-N-benzyl)aminomethyl!-imidazoledihydrochloride (Compound 4), m.p. 239°-240° C.

(d) 2-(2-Methoxyphenyl)-4(5)- (N,N-dimethyl)aminomethyl!-imidazoledihydrochloride (Compound 5), melting at X° C.

(e) 2-(3-Methoxyphenyl)-4(5)- (N-methyl-N-benzyl)aminomethyl!-imidazoledihydrochloride (Compound 6), m.p. 115°-117° C.

(f) 2-(2,3-Dimethoxyphenyl)-4(5)- (N,N-dimethyl)aminomethyl!-imidazoledihydrochloride (Compound 7), m.p. 220°-221° C.

(g) 2-(2,3-Dimethoxyphenyl)-4(5)-(N-methyl-N-benzyl)aminomethyl!-imidazole dihydrochloride (Compound 8),m.p. 200°-202° C.

(h) 2-(3-Methoxyphenyl)-4(5)- (N,N-diethyl)aminomethyl!-imidazoledihydrochloride (Compound 9), m.p. 213°-214° C.

(i) 2-(3-Fluorophenyl)-4(5)- (N,N-dimethyl)aminomethyl!-imidazoledihydrochloride (Compound 10), m.p. 211°-214° C.

(j) 2-(2-Fluorophenyl)-4(5)- (N-methyl-N-benzyl)aminomethyl!-imidazoledihydrochloride (Compound 11), m.p. 241°-244° C.

(k) 2-(3-Methylphenyl)-4(5)- (N,N-dimethyl)aminomethyl!-imidazoledihydrochloride (Compound 12), m.p. 231°-234° C.

(l) 2-(2-Fluorophenyl)-4(5)- (N,N-dimethyl)aminomethyl!-imidazoledihydrochloride (Compound 13), m.p. 246°-247° C.

(m) 2-(4-Fluorophenyl)-4(5)- (N-methyl-N-benzyl)aminomethyl!-imidazoledihydrochloride (Compound 14), m.p. 237°-239° C.

(n) 2-(2-Methoxyphenyl)-4(5)- (N-methyl-N-benzyl)aminomethyl!-imidazoledihydrochloride (Compound 15), m.p. 239°-24l° C.

(o) 2-(5-Bromo-2,3-dimethoxyphenyl)-4(5)-(N,N-dimethyl)aminomethyl!-imidazole dihydrochloride (Compound 16), m.p.194°-194° C.

(p) 2-(5-Bromo-2-methoxyphenyl)-4(5)-(N-methyl-N-benzyl)aminomethyl!-imidazole dihydrochloride (Compound 17),m.p. 242°-243° C.

(q) 2-(5-Bromo-2,3-dimethoxyphenyl)-4(5)-(N-methyl-N-benzyl)aminomethyl!-imidazole dihydrochloride (Compound 18).

EXAMPLE VII ##STR55##

A mixture of 350 mg 2-phenyl-4-hydroxymethylimidazole and 3 mL thionylchloride was heated at 80° C. for 15 min. The excess thionyl chloridewas removed in vacuo and the residue was dissolved in 20 mL of methylenechloride. This solution was added to a mixture of 1 mL triethylamine and410 mg 1-(2-methoxyphenyl)piperazine in 20 mL methylene chloride and themixture was stirred for 20 min. The solvents were removed in vacuo andthe residue was dissolved in 2N HCl and washed two times with ethylacetate. The aqueous layer was made basic with 50% NaOH and the productwas extracted with methylene chloride. The organic extracts were driedover magnesium sulfate, the solvents removed in vacuo, and the residuewas crystallized from ethyl acetate to afford 2-phenyl-4(5)-(4-(2-methoxyphenyl)-piperazin-1-yl)-methyl!imidazole (Compound 19),m.p. 105°-107° C.

EXAMPLE VIII

The following compounds were prepared essentially according to theprocedure described in Example VII:

(a) 2-(4-Fluorophenyl)-4(5)-(4-(2-methoxyphenyl)-piperazin-1-yl)-methyl!-imidazole (Compound 20),m.p. 95°-97° C.

(b) 2-(2,3-Dimethoxyphenyl)-4(5)-(4-(2-methoxyphenyl)-piperazin-1-yl)-methyl!-imidazole dihydrochloride(Compound 21 ), m.p. 217°-218° C.

(c) 2-(3-Chlorophenyl)-4(5)-(4-(2-methoxyphenyl)-piperazin-1-yl)-methyl!-imidazole dihydrochloride(Compound 22), m.p. 198°-199° C.

(d) 2-Phenyl-4(5)- (4-(2-pyrimidinyl)-piperazin- 1-yl)-methyl!-imidazoledihydrochloride (compound 23), m.p. 246°-248° C.

(d') 2-Phenyl-4(5)- (4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazoledimaleate (compound 23A), m.p. 176°-178° C.

(e) 2-Phenyl-4(5)- (4-(2-pyridyl)-piperazin-1-yl)-methyl!-imidazoledihydrochloride (Compound 24), m.p. 176°-177° C.

(f) 2-Phenyl-4(5)- (4-benzyl-piperidin-1-yl)-methyl!-imidazoledihydrochloride (Compound 25), m.p. 234°-236° C.

(g) 2-Phenyl-4(5)- (4-phenyl-piperidin-1-yl)-methyl!-imidazoledihydrochloride (Compound 26), m.p. 238°-240° C.

(h) 2-Phenyl-4(5)-(1,2,3,4-tetrahydroisoquinolin)-2-yl-methyl!-imidazole dihydrochloride(Compound 27).

(i) 2-Phenyl-4(5)-2-phenyl-5,6,7,8-tetrahydrobenzimidazole imidazoledihydrochloride (Compound 76).

EXAMPLE IX

The following compounds were prepared essentially according to theprocedures described in Examples I-VII:

(a) 2-(2,3-Dimethoxyphenyl)-4(5)-(1,2,3,4-tetrahydroisoquinolin)-2-yl-methyl!-imidazole dihydrochloride(Compound 28), m.p. 205°-207° C.

(b) 2-(4-Methoxyphenyl)-4(5)- (N-methyl-N-benzyl)aminomethyl!-imidazoledihydrochloride (Compound 29).

(c) 2-(3,4-Dimethoxyphenyl)-4(5)-(N-methyl-N-benzyl)aminomethyl!-imidazole dihydrochloride (Compound 30).

(d) 2-(3-Methoxyphenyl)-4(5)- (N-methyl)aminomethyl!-imidazoledihydrochloride (Compound 31).

(e) 2-(5-Chloro-2-methoxyphenyl)-4(5)-(N-methyl-N-benzyl)aminomethyl!-imidazole (Compound 32), m.p. 88°-89° C.

(f) 2-(5-Chloro-2-methoxyphenyl)-4(5)-(N,N-dimethyl)aminomethyl!-imidazole dihydrochloride (Compound 33), m.p.231°-233° C.

(g) 2-(5-Chloro-2-methoxyphenyl)-4(5)- (N-methyl)aminomethyl!-imidazoledihydrochloride (Compound 34), m.p. 225°-227° C.

(h) 2-(5-Chloro-2-methoxyphenyl)-4(5)- (N-benzyl)aminomethyl!-imidazoledihydrochloride (Compound 35), m.p. 184°-186° C.

(i) 2-(5-Chloro-2-benzyloxyphenyl)-4(5)-(N-methyl-N-benzyl)aminomethyl!-imidazole dihydrochloride (Compound 36),m.p. 118°-123° C.

(j) 2-(2-Benzyloxyphenyl)-4(5)-(N-methyl-N-benzyl)aminomethyl!-imidazole dihydrochloride (Compound 37),m.p. 199°-200° C.

(l) 2-(3-Ethylphenyl)-4(5)- (N-methyl-N-benzyl)aminomethyl!-imidazoledihydrochloride (Compound 38), m.p. 234°-235° C.

(m) 2-(5-Chloro-2-methoxyphenyl)-4(5)-(N-methyl-N-(-4-chlorobenzyl))aminomethyl!-imidazole dihydrochloride(Compound 39), m.p. 186°-188° C.

(n) 2-(5-Chloro-2-hydroxyphenyl)-4(5)-(N-methyl-N-benzyl)aminomethyl!-imidazole dihydrochloride (Compound 40),m.p. 227°-228° C.

(o) 2-(5-Bromo-2-benzyloxyphenyl)-4(5)-(N-methyl-N-benzyl)aminomethyl!-imidazole dihydrochloride (Compound 41).

(p) 2-(5-Ethyl-2-methoxyphenyl)-4(5)-(N-methyl-N-benzyl)aminomethyl!-imidazole dihydrochloride (Compound 42),m.p. 114°-115° C.

(q) 2-(5-Chloro-2-methoxyphenyl)-4(5)-(4-(2-methoxyphenyl)-piperazin-1-yl)-methyl!-imidazole dihydrochloride(Compound 43), m.p. 138°-143° C.

(r) 2-(5-Chloro-2-methoxyphenyl)-4(5)-(4-phenyl-piperidin-1-yl)-methyl!-imidazole dihydrochloride (Compound44), m.p. 138°-143° C.

(s) 2-Phenyl-4(5)- (4-phenyl-piperazin-1-yl)methyl!imidazole (Compound45), m.p. 189°-191° C.

(t) 2-(4-Fluorophenyl)-4(5) (4-phenyl-piperidin-1-yl)-methyl!-imidazoledihydrochloride (Compound 46), m.p. 260°-264° C. (dec).

(u) 2-(4-Methoxyphenyl)-4(5) (4-phenyl-piperidin-1-yl)-methyl!-imidazoledihydrochloride (Compound 47), m.p. 196°-199° C.

(v) 2-Phenyl-4(5)-(4-(3-trifluoromethylphenyl)-piperazin-1-yl-)methyl!imidazole (Compound48), m.p. 182°-184° C.

(w) 2-(2-Methoxyphenyl)-4(5),(4-phenyl-piperidin-1-yl)-methyl!-imidazole dihydrochloride (Compound49).

(x) 2-(3-Methoxyphenyl)-4(5) (4-phenyl-piperidin-1-yl)-methyl!-imidazoledihydrochloride (Compound 50), m.p. 114°-117° C.

(y) 2-(3-Fluorophenyl)-4(5) (4-phenyl-piperidin-1-yl)-methyl!-imidazole(Compound 51), m.p. 110°-112° C.

(z) 2-(2-Fluorophenyl)-4(5) (4-phenyl-piperidin-1-yl)-methyl!-imidazoledimaleate (Compound 52), m.p. 142°-144° C.

(aa) 2-(2-Methylphenyl)-4(5)-(4-benzyl-piperidin-1-yl)-methyl!-imidazole dihydrochloride (Compound53), m.p.242°-244° C.

(ab) 2-(5-Ethyl-2-methoxyphenyl-4(5)-(4-phenyl-piperidin-1-yl)-methyl!-imidazole dihydrochloride (Compound54), m.p.76°-78° C.

(ac) 2-(5-Ethyl-2-methoxyphenyl-4(5)-(4-(2-methoxyphenyl)-piperazin-1-yl)-methyl!-imidazole dihydrochloride(Compound 55), m.p.61°-64° C.

(ad) 2-Phenyl-4(5)- (4(4-fluorophenyl)-piperazin-1-yl-)methyl!imidazoledihydrochloride (Compound 56), m.p.64°-68° C.

(ae) 2-(5-Ethyl-2-methoxyphenyl-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole dihydrochloride(Compound 57), m.p.75°-78° C.

(af) 2-Phenyl-4(5)-(4(5-fluoro-2-pyrimidinyl)-piperazin-1-yl)-methyl!imidazoledihydrochloride (Compound 58), m.p. 188°-190° C.

(ag) 2-(4-Fluorophenyl)-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole dihydrochloride(Compound 59), m.p. 181°-184° C.

(ah) 2-Phenyl-4(5)-(4(5-chloro-2-methylphenyl)-piperazin-1-yl-)-methyl!imidazoledihydrochloride (Compound 60), m.p. 142°-145° C.

(ai) 2-Phenyl-4(5)-(4(3,4-dichlorophenyl)-piperazin-1-yl-)methyl!imidazole (Compound 61),m.p. 179°-181° C.

(aj) 2-Phenyl-4(5)- (4(4-fluorophenyl)-piperidin-1-yl-)methyl!imidazoledimaleate(Compound 62), m.p. 148°-149° C.

(ak) 2-(3-Fluorophenyl)-4(5)-(4-benzyl-piperidin-1-yl)-methyl!-imidazole dimaleate (Compound 63).m.p.148°-149° C.

(al) 2-(4-Fluorophenyl)-4(5)-(4-benzyl-piperidin-1-yl)-methyl!-imidazole dihydrochloride (Compound64), m.p. 254°-256° C.

(am) 2-Phenyl-4(5)-(4-(4-fluorobenzyl)-piperidin-1-yl)-methyl!-imidazole dihydrochloride(Compound 65).

(an) 2-(2-Fluorophenyl-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole (Compound 66),m.p.159°-161° C.

(ao) 2-(4-Methylphenyl-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole (Compound 67), m.p.176°-179° C.

(ap) 2-(2-Fluorophenyl)-4(5)-(4-benzyl-piperidin-1-yl)-methyl!-imidazole dimaleate (Compound 68),m.p. 113°-115° C.

(aq) 2-(4-Chlorophenyl-4(5)-(4-(2-pyridyl)-piperazin-1-yl)-methyl!-imidazole (Compound 69), m.p.176°-177° C.

(ar) 2-Phenyl-4(5)-(4-(5-fluoro-2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole dimaleate(Compound 70), m.p. 185°-186° C.

(as) 2-(2-Fluorophenyl-4(5)-(4-(5-fluoro-2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole dimaleate(Compound 71), m.p. 172°-173° C.

(at) 2-(4-Fluorophenyl-4(5)-(4-(5-fluoro-2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole dimaleate(Compound 72), m.p. 183°-184° C.

EXAMPLE X ##STR56##

A solution of 40 mL tetrahydrofuran containing 1.0 g of2-phenylimidazole was cooled to 0° C. and 4 mL of 2M lithiumdiisopropylamide was added dropwise which resulted in the formation of awhite suspension. The mixture was stirred for 10 min at 0° C. and then0.7 mL of dimethyl sulfate was added. The reaction was allowed to stirat room temperature for an additional 30 min during which time thesolution became homogeneous. Aqueous ammonium chloride was added and thetetrahydrofuran was removed by evaporation under reduced pressure. Theaqueous phase was extracted with 2×100 mL aliquots of dichloromethane.The combined organic extracts were washed with dilute ammonium hydroxideand brine. The combined organic extracts were dried over anhydroussodium sulfate and concentrated under reduced pressure to yield 1 g of1-methyl-2-phenylimidazole which was used in the next step withoutfurther purification or characterization.

To a solution of 1 g of 1 methyl-2-phenylimidazole in 10 mL acetic acidwere added 0.4 mL of 37% aqueous formaldehyde and 1.2 mL of4-benzylpiperidine. The reaction mixture was heated at 100° C. for 10hours and the acetic acid then removed by evaporated under reducedpressure. The residue was dissolved in water and made alkaline with 5%sodium hydroxide and extracted with 2×100 mL of dichloromethane. Thecombined extracts were dried over anhydrous sodium sulfate andconcentrated to small volume under reduced pressure to give 1methyl-2-phenyl-4- (4-benzylpiperidin-1-yl)methyl!-imidazole.

The following compounds were prepared essentially according to theprocedure described in Example X utilizing 2-phenyl-4(5)-(4-(2-pyrimidinyl)piperazin-1-yl)methylimidazole (Compound 22) asstarting material. The resulting isomers were separated bychromatography on silica gel using ethyl acetate as eluant.

a) 1-Methyl-2-phenyl-4-(4-(2-pyrimidinyl)piperazin-1-yl)methyl!-imidazole (Compound 74).

b) 1-Methyl-2-phenyl-5-(4-(2-pyrimidinyl)piperazin-1-yl)methyl!-imidazole (Compound 75).

EXAMPLE XI ##STR57##

A mixture of 3g of ethylthiooxamate, 4.25 g of 2-aminoacetophenonehydrochloride and 3.69 g of sodium acetate was dissolved in 20 mL ofacetic acid and heated under reflux for 3 hr. The reaction mixture wasallowed to cool to room temperature and the acetic acid removed byevaporation under reduced pressure. The residue was basified withaqueous sodium carbonate and extracted with 2×100 mL of ethyl acetate.The combined extracts were washed with 2×100 mL of brine, dried overanhydrous sodium sulfate and the solvent removed under reduced pressureto yield 2.8 g of ethyl 4-phenylimidazole-2-carboxylate as a solid whichwas used in the next step without further purification orcharacterization.

To a solution of 2.75 g ethyl-4-phenylimidazole-2-carboxylate in 20 mLtetrahydrofuran was added a suspension of 0.5 g lithium aluminum hydridein 30 mL of tetrahydrofuran. The reaction mixture was stirred at roomtemperature overnight, poured into 100 mL of ice water and extractedwith 2×100 mL of ethyl acetate. The combined extracts were washed with2×100 mL of brine, dried over anhydrous sodium sufate and the solventremoved under reduced pressure to yield 2 g of2-hydroxymethyl-4-phenylimidazole which was used in the next stepwithout further purification or characterization.

A solution of 1 g of 2-hydroxymethyl-4-phenylimidazole in 10 mL ofthionyl chloride was heated at 60° C. for 1 hr. After removal of excessthionyl chloride by evaporation under reduced pressure, the residue wastreated with a solution of 1 g 4-benzylpiperidine and 2 gN,N,-diisopropylethylamine in 50 mL of chloroform. The reaction mixturewas stirred at 60° C. for 1 hr, allowed to cool to room temperature andwashed successively with 50 mL of 1N sodium hydroxide solution and 50 mLof water. The organic phase was then dried over anhydrous sodium sulfateand the solvent evaporated under reduced pressure to yield 850 mg of4-phenyl-2(5)- (4-benzylpiperidin-1-yl)-methyl!imidazole which wasconverted into its monofumarate salt (Compound 77), mp 155°-157 ° C.

EXAMPLE XII

The following compounds were prepared essentially according to theprocedure described in Example XI.

(a) 4-Phenyl-2(5)- (N-methyl-N-benzyl)aminomethyl!-imidazoledihydrochloride (Compound 78), m.p. 229°-231° C.

(b) 4-Phenyl-2(5)- (4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazoledihydrochloride (Compound 79), m.p. 178°-180° C.

(c) 4-Phenyl-2(5)- 4-(4-fluoro-benzyl-piperidin-1-yl)-methyl!-imidazoledihydrochloride (Compound 80), m.p. 216°-218° C.

(d) 4-Phenyl-2(5)- (4-phenyl-piperidin-1-yl)-methyl!-imidazoledihydrochloride (Compound 81 ), m.p. 182°-184° C.

(e) 4-Phenyl-2(5)- (4(4-fluorophenyl)-piperazin-1-yl-)methyl!imidazoledihydrochloride (Compound 82), m.p. 161°-163° C.

(f) 4-Phenyl)-2(5)-(4-(2-methoxyphenyl)-piperazin-1-yl)-methyl!-imidazole dihydrochloride(Compound 83), m.p. 229°-231 ° C.

(g) 4-Phenyl-2(5)- (4-(2-pyridyl)-piperazin-1-yl)-methyl!-imidazoletrihydrochloride (Compound 84), m.p. 165°-167° C.

(h) 4-Phenyl-2(5)- (4-phenyl-piperazin-1yl-)methyl!imidazoledihydrochloride (Compound 85), m.p. 182°-184° C.

(i) 4-Phenyl-2(5)- (4-benzoyl-piperidin-1-yl)-methyl!-imidazoledihydrochloride (Compound 86) m.p. 200°-202° C.

(j) 4-Phenyl-2(5)- 4-(4-fluoro-benzoyl-piperidin-1-yl)-methyl!-imidazoledihydrochloride (Compound 87), m.p. 173°-175° C.

EXAMPLE XIII ##STR58##

A solution of 10 g of 2-bromopropiophenone in 50 mL formamide was heatedat 180° C. overnight. The reaction was then allowed to cool to roomtemperature and poured into 250 mL ice water. The mixture was adjustedto pH 9 with 1N sodium hydroxide and the resulting precipitate wascollected by filtration, washed with water and dried to yield 6.0 g of4-methyl-5-phenylimidazole as a solid which was used in the next stepwithout further purification.

A mixture of 128 mg 4-methyl-5-phenylimidazole, 180 mg of4-benzylpiperidine and 85 mg of 37% formaldehyde in 10 mL acetic acidwas heated under reflux for 8 hr. The acetic acid was then removed byevaporation under reduced pressure and the residue was dissolved in 50mL ethyl acetate. The ethyl acetate solution was washed successivelywith 50 mL of dilute sodium hydroxide solution and water. The ethylacetate extract was then dried over anhydrous sodium sulfate and thesolvent removed by evaporation under reduced pressure to yield5-methyl-4-phenyl-2(5)- (4-benzyl-piperidin-1-yl)-methyl!imidazole as anoil which was purified by chromatography on silica gel using 5% methanolin methylene chloride as eluent. Treatment of the purified free basewith ethanolic HCl yielded 5-methyl-4-phenyl-2(5)-(4-benzyl-piperidin-1-yl)-methyl!imidazole dihydrochloride (Compound88).

EXAMPLE XIV ##STR59##

To a solution of 14.3 g 2-phenyl-4(5)-methylimidazole and 13.8 g of1-(2-pyrimidyl)piperazine in 50 mL of ethanol was added a solution of7.1 mL of aqueous formaldehyde. The resulting mixture was heated atreflux temperature for 2 hr and allowed to cool to room temperature. Thesolid was collected by filtration and dried to yield 20 g of2-phenyl-5-methyl-4(5)-(4-(2-pyrimidinyl)piperazin-1-yl)methyl!imidazole which was treated with2 equivalents of maleic acid in isopropanol to yield2-phenyl-5-methyl-4(5)-(4-(2-pyrimidinyl)piperazin-1-yl)methyl!-imidazole dimaleate (Compound89), m.p. 172°-174° C.

EXAMPLE XV ##STR60##

To a solution of 100 mg of 2-phenyl-4(5)-(4-(2-pyrimidinyl)piperazin-1-yl)methyl!imidazole in 10 mL of chloroformwas added one equivalent (80 mg) of iodine in 5 mL of chloroformfollowed by 0.5 mL of triethylamine. The reaction mixture was stirred atroom temperature for 30 min during which time a solid crystallized fromthe solution. The solid was collected by filtration to yield 52 mg of2-phenyl-5-iodo-4(5)- (4-(2-pyrimidinyl)piperazin-1-yl)methyl!-imidazolehydroiodide salt (Compound 90) which had a m.p. of 196°-199° C.

EXAMPLE XVI ##STR61##

To a solution of 220 mg of 2-phenyl-4-imidazole carboxaldehyde in 5 mLof tetrahydrofuran was added 6.4 mL of a 1L methyllithium solution intetrahydrofuran. The reaction mixture was quenched with 50 mL of waterand the mixture extracted with 2×50 mL aliquots of ethyl acetate. Thecombined ethyl acetate extracts were dried over anhydrous sodiumsulfate, filtered and the solvent evaporated under reduced pressure toyield 250 mg of 2-phenyl-4(5)-(1-hydroxyethyl)imidazole which was usedin the next step without further purification or characterization. Theresidue of 2-phenyl-4(5)-(1-hydroxyethyl)imidazole was dissolved in 8mLof thionyl chloride and heated at reflux temperature for 30 rain afterwhich the thionyl chloride was removed by distillation under reducedpressure to yield 250 mg of 2-phenyl-4(5)-(1-chloroethyl)imidazole as anoil which was used in the next step without additional purification orcharacterisation. This oil was dissolved in 10 mL of chloroform and tothis solution was added 224 mg of 4-benzylpiperidine and 2 mL oftriethylamine. The reaction was allowed to stand at room temperature for10 min and then washed with 50 mL 1N sodium hydroxide. The chloroformextract was then separated and dried over anhydrous sodium sulfate,filtered and the solvent removed by evaporation under reduced pressureto yield 2-phenyl-4(5)- 1-((4-benzyl-piperidin-1-yl)-ethyl)}imidazolewhich was purified by chromatography on silica gel using 10%methanol/dichloromethane as eluent. Treatment with ethanolic HCl yielded2-phenyl-4(5)- 1-((4-benzyl-piperidin-1-yl)-ethan-1-yl)!imidazoledihydrochloride salt (Compound 91), m.p. 169°-171° C.

EXAMPLE XVII ##STR62##

A solution of 5.5 g 1-cyanonaphthalene in 150 mL dry ether was cooled to0° C. To this solution 12.1 g lithium bis(trimethylsilyl)amide was addedin one portion. The mixture was stirred for 12 hours and allowed to warmto room temperature. The reaction mixture was cooled to 0° C. thenquenched by the addition of 200 mL 3N HCl. After stirring 20 minutes at0° C., the mixture was transferred to a separatory funnel and washed3×100 mL ether. The aqueous layer was cooled on an ice bath and adjustedto pH 14 with solid sodium hydroxide. This solution was extracted4×100mL dichloromethane. The combined organic extracts were washed2×100mL water, 1×100 mL brine, dried over potassium carbonate, filtered,then concentrated under reduced pressure to give 3.6 g of the desiredamidine which was used without further purification.

A mixture of 3.6 g of the crude amidine, 2.5 g of dihydroxyacetonedimer, and 2.5 g of ammonium chloride were suspended in 35 mL conc.ammonium hydroxide in a pressure tube. The mixture was heated to 90° C.for 3 hours during which time the amidine dissolved and the productprecipitated out. The reaction mixture was cooled to room temperatureand the product collected by filtration, washed with cold water, anddried in vacuo to give 3 g 2-(1-naphthyl)-4(5)-(hydroxymethyl)imidazoleas off-white crystals, m.p. 155°-158° C.

A solution of 62 mg 2-(1-naphthyl)-4(5)-(hydroxymethyl)imidazole wasdissolved in 3 mL of thionyl chloride and warmed to 60° C. for 2 hours.The solvent was removed and the residue was dissolved in 3 mL chloroformand 53 mg 4-benzylpiperidine was added followed by 47 mg ofdiisopropylethylamine. The reaction mixture was stirred at roomtemperature for 1 hour, diluted with 3 volumes of chloroform, thenwashed 3×3 mL of 10% sodium hydroxide. The organic layer was dried overanhydrous sodium sulfate, filtered, then concentrated under reducedpressure. The residue was purified by chromatography on silica geleluting with 5% methanol in dichloromethane to yield 62 mg of2-(1-naphthyl)-4(5)- (4-benzyl-piperidin-1-yl)-methyl!imidazole(Compound 92), m.p. 81°-83° C.

EXAMPLE XVIII

The following compounds were prepared from the corresponding nitrilesessentially according to the procedures described in Example XVII.

(a) 2-(1-Naphthyl)-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole (Compound 93), m.p.187°-188° C.

(b) 2-(1-Naphthyl)-4(5)-(4-(2-pyridyl)-piperazin-1-yl)-methyl!-imidazole (Compound 94), m.p.182°-183° C.

(c) 2-(1-Naphthyl)-4(5)- (N-methyl-N-benzyl)-methyl!-imidazole (Compound95), m.p. 74°-76° C.

(d) 2-(2-Naphthyl)-4(5)- (4-benzyl-piperidin-1-yl)-methyl!-imidazole(Compound 96), m.p. 92°-94° C.

(e) 2-(2-Naphthyl)-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole (Compound 97),m.p.218°-219° C.

(f) 2-(2-Naphthyl)-4(5)-(4-(2-pyridyl)-piperazin-1-yl)-methyl!-imidazole(Compound 98), m.p.199°-201° C.

(g) 2-(2-Naphthyl)-4(5)- (N-methyl-N-benzyl)-methyl!-imidazole(Compound99), m.p. 86°-87° C.

(h) 2-(2-Pyridyl)-4(5)- (4-benzyl-piperidin-1-yl)-methyl!-imidazole(Compound 100), m.p. 96°-98° C.

(i) 2-(2-Pyridyl)-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole (Compound 101),m.p. 134°-135° C.

(j) 2-(2-Pyridyl)-4(5)- (4-(2-pyridyl)-piperazin-1-yl)-methyl!-imidazole(Compound 102), m.p. 135°-137° C.

(k) 2-(2-Pyridyl)-4 (5)- (N-methyl-N-benzyl)-methyl!-imidazole (Compound103), m.p. 61°-63° C.

(1) 2-(3-Pyridyl)-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole (Compound 104),m.p. 155°-157° C.

(m) 2-(3-Pyridyl)-4(5)- (N-methyl-N-benzyl)-methyl!-imidazole (Compound105), m.p. 141°-142° C.

(n) 2-(4-Pyridyl)-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole (Compound 106),m.p. 154°-156° C.

(o) 2-(2-Pyrazinyl)-4(5)- (4-benzyl-piperidin-1-yl)-methyl!-imidazole(Compound 107), m.p. 80°-81° C.

(p) 2-(2-Pyrazinyl)-4(5)-(4-(2-pyrimidinyl)-piperizin-1-yl)-methyl!-imidazole (Compound 108),m.p. 164°-165° C.

(q) 2-(2-Pyrazinyl)-4 (5)- (N-methyl-N-benzyl)-methyl!-imidazole(Compound 109), m.p. 93°-94° C.

(r) 2-(2-Thienyl)-4(5)- (4-benzyl-piperidin- t-yl)-methyl!-imidazole(Compound 110), m.p. 77°-79° C.

(s) 2-(2-Thienyl)-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole (Compound 111),m.p. 204°-205° C.

(t) 2-(2-Thienyl)-4 (5)- (N-methyl-N-benzyl)-methyl!-imidazole (Compound112), m.p. 132°-134° C.

(u) 2-(2-Thienyl)-4(5)- (4-(2-pyridyl)-piperazin-1-yl)-methyl!-imidazole(Compound 113), m.p. 179°-181° C.

(v) 2-(2-Quinolinyl)-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole (Compound 114),m.p. 263° C. (dec).

(w) 2-(2-Quinolinyl)-4 (5)- (N-methyl-N-benzyl)-methyl!-imidazole(Compound 115), m.p. 247° C. (dec).

EXAMPLE XIX ##STR63##

A solution was prepared by dissolving 193 mg of 2-benzoylimidazole, 330mg of 1-(2-pyrimidyl)-piperazine and 165 mL of a 37% solution offormaldehyde in 1 mL of acetic acid and the resulting mixture was heatedto 100° C. for 15 hours. The mixture was then cooled to 0° C., basifiedwith 3 N hydrochloric acid, then extracted with 5×10 mL of ethylacetate. The organic extracts were washed with 2×10 mL water, 1×10 mL ofbrine, dried over anhydrous sodium sulfate, filtered, then concentratedunder reduced pressure. The residue was chromatographed on silca gelusing 5% methanol in dichloromethane as eluent to yield 43 mg of2-(benzoyl)-4(5)- (4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole(Compound 116), m.p. 177°-179° C.

EXAMPLE XX

The following compounds were prepared essentially according to theprocedures described in Example XVII.

a) 2-Benzyl-4(5)- (4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole(Compound 117), m.p. 160°-161° C.

(b) 2-(5-Methoxy-3,4-dihydro-naphth-1-yl)-4(5)-(N-methyl-N-benzyl)-methyl!-imidazole (Compound 118), m.p. 133°-134° C.

EXAMPLE XXI ##STR64##

A solution of 1.25 g of 2-phenyl-4(5)-imidazole propenoic acid wasdissolved in 20 mL thionyl chloride and heated at reflux temperature for2 hours. The solvent was removed and the residue suspended in 20 mLchloroform. To this solution was added 1.7 g of1-(2-pyrimidinyl)-piperazine dihydrogen chloride followed by 3.5 mL ofdiisopropylethylamine. The reaction mixture was stirred for 6 hours atroom temperature then diluted with 50 mL chloroform, washed with 3×20 mLof 10% sodium hydroxide solution, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waschromatographed on silica gel using 5 % methanol in dichloromethane aseluent to yield 554 mg of 2-phenyl-4(5)-(4(2-pyrimidinyl)-piperazin-1-yl)-propen-1-oyl!-imidazole (Compound119),m.p. 235°-236° C.

EXAMPLE XXII

The following compounds were prepared according to the proceduredescribed in Example XXI:

(a) 2-Phenyl-4(5)- (4-phenyl-piperazin-1-yl)-propen-1-oyl!-imidazole(Compound 120), m.p. 151°-152° C.

(b) 2-Phenyl-4(5)-(4-hydroxy-4-(4-chlorophenyl)-piperidin-1-yl)-propen-1-oyl!-imidazole(Compound121), m.p. 236°-240° C.

EXAMPLE XXIII ##STR65##

A solution of 68 mg 2-phenyl-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-propen-1-oyl!-imidazole was dissolveda mixture of in 2 mL ethyl acetate and 0.2 ml ethanol and the suspensionwas stirred for 2 days under a H2 atmosphere using 20 mg Pt on carbon ascatalyst. The mixture was filtered through Celite and the solventremoved. The residue was chromatographed on silca gel using 5 %methanol/dichloromethane as eluent to yield 37 mg 2-phenyl-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-propan-1-oyl!-imidazole (Compound122), m.p. 143°-148° C.

EXAMPLE XXIV

The following compounds were prepared according to the proceduredescribed in Example XXIII

(a) 2-Phenyl-4(5)- (4-phenyl-piperazin-1-yl)-propan-1-oyl!-imidazole(Compound 123), m.p. 180°-183° C.

(b) 2-Phenyl-4(5)-(4-(2-(3,4,5,6-tetrahydro)-pyrimidinyl)-piperazin-1-yl)-propan-1-oyl!-imidazole(Compound 124), m.p. 210°-211° C.

EXAMPLE XXV ##STR66##

To a solution of 84 mg 2-phenyl-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-propan-1-oyl!-imidazole in 5 mL drytetrahydrofuran at room temperature was added 18 mg of lithium aluminumhydride and the mixture was heated at reflux temperature refluxed for 2hours. After quenching with ethyl acetate, the solvent was removed underreduced pressure. The residue was chromatographed on silca gel using 10% methanol in dichloromethane as eluent to yield 20 mg of 2-phenyl-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-propan-1-yl!-imidazole (Compound125), m.p. 133°-135° C.

EXAMPLE XXVI

The following compounds were prepared according to the proceduredescribed in Example XXV.

(a) 2-Phenyl-4(5)- (4-phenyl-piperazin-1-yl)-propan-1-yl!-imidazole(Compound 126), m.p. 50°-54° C.

(b) 2-Phenyl-4(5)-(4-hydroxy-4-(4-chlorophenyl)-piperidin-1-yl)-propan-1-yl!-imidazole(Compound 127), m.p. 122°-124° C.

EXAMPLE XXVII ##STR67##

To a solution of 6.8 g of 2-phenylimidazole in 200 mL 3N hydrochloricacid was added 5% Rhodium on Carbon, Degussa type G10 NB/W. The mixturewas hydrogenated at 100 psi for 24 hours then filtered through celite.The solution was neutralized with 25% sodium hydroxide and extractedwith 2×100 mL ethyl acetate. The combined extract was washed with 200 mLof brine and dried over anhydrous sodium sulfate. Evaporation of thesolvent gave 2-cyclohexylimidazole as a fluffy, white solid which wasused in the next step without further purification or characterization.

To a solution of 25 1 mg 2-cyclohexylimidazole in 8 mi., of acetic add,274 mg of 1-(2-pyrimidyl)piperazine and 88 microliters of 37%formaldehyde were added. The solution was heated at 100° C. for 12 hoursthen the solvent was removed under reduced pressure and the residue wasdiluted with water. The mixture was made slightly alkaline with 5%sodium hydroxide and then extracted with 2×25 mL of ethyl acetate. Thecombined extracts were washed with 25 mL of brine, dried over anhydroussodium sulfate and the solvent removed by evaporation under reducedpressure. The products were separated on reverse phase silica gel(Whatman PLKC18F) using 0.2M aqueous sodium chloride with 80% methanol.Evaporation of the individual fractions yielded2-cyclohexyl-4(5)-hydroxymethyl imidazole and 50 mg of the desired2-cyclohexyl-4(5)- (4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole(Compound 128), m.p.210°-213° C.

EXAMPLE XXVIII

The following compounds were prepared essentially according to theprocedure described in Example XXVII.

(a) 2-cyclohexyl-4(5)- (4-benzyl-piperidin-1-yl)-methyl!-imidazole(Compound 129), m.p. 185°-188° C.

(b) 2-cyclohexyl-4(5)- (N-methyl-N-benzyl)-methyl!-imidazole (Compound130), m.p.235°-238° C.

(c) 2-(4-methylcyclohexyl)-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole (Compound 131).

EXAMPLE XXIX ##STR68##

A solution of 790 mg of iodine in 5 mL of chloroform was added to 1.0 gof 2-phenyl-4(5)- (4-(2-pyrimidinyl)piperazin-1-yl)methyl!imidazoledissolved in 30 mL of chloroform at ambient temperature. After thesolution was stirred for 10 minutes 1 mL of triethylamine was added andstirring was continued until no more solids formed. The solid wascollected by filtration and after drying yielded 700 mg of2-phenyl-5-iodo4(5)- (4-(2-pyrimidinyl)piperazin-1-yl)methyl!-imidazolewhich was used in the next step without further purification orcharacterization.

To a solution of 53 mg 2-phenyl-5-iodo-4(5)-(4-(2-pyrimidinyl)piperazin-1-yl)methyl!-imidazole in 1 mL ofdimethylformamide was added 130 microliters of phenyltrimethylstannaneand 3 mg of bis(triphenylphosphine)-palladium(II) chloride. The reactionmixture was heated at 100° C. for 4 hours then poured into water andextracted with 2×10 mL of ethyl acetate and washed with 10 mL of 10%ammonium hydroxide. The combined organic extracts were dried overanhydrous sodium sulfate and the solvent removed by evaporation underreduced pressure. The resulting material was chromatographed on silicagel with 5% methanol in dichloromethane as eluant to yield 15 mg of2,5-diphenyl-4(5)- (4-(2-pyrimidinyl)piperazin-1-yl)methyl!-imidazole(Compound 132), m.p. 221°-225° C.

EXAMPLE XXX ##STR69##

To a solution of 12.4 g p-tolunitrile in 500 mL of diethyl ether wasadded 23 g of solid lithium bis(trimethylsilyl)amide at ambienttemperature. The mixture was stirred for 2 hours then hydrolysed with10% HCl at 0° C. The mixture was stirred for an additional 30 minutesand then concentrated to dryness to yield 6 g of 4-methylbenzamidinehydrochloride which was used in the next step without furtherpurification

A solution of 4 g 4-methylbenzamidine hydrochloride in 60 mL ammoniumhydroxide was treated with 4.0 g with dihydroxyacetone and 4.8 gammonium chloride. The reaction mixture was heated to 90° C. for 4 hoursin a sealed tube. On cooling to more temperature a the solid formed wascollected by filtration to yield 3.0 g2-(4-methylphenyl)-5-hydroxymethyl-imidazole which was convertedaccording to the procedure described in Example VII to yield2-(4-methylphenyl-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole (Compound 133),m.p. 178°-180° C.

EXAMPLE XXXI

The following compounds were prepared according to the proceduredescribed in Example XXX.

(a) 2-(4-Iodophenyl-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-imidazole (Compound 134), m.p.218 °-220° C.

(b) 2-Phenyl-4(5)-(4-(4-chlorophenyl)-3-methylpiperazin-1-yl)methyl!imidazole (Compound135), m.p. 137°-139° C.

(c) 2-Phenyl-4(5)-(4-(4-methylphenyl)-3-methylpiperazin-1-yl)methyl!imidazole (Compound136), m.p. 172°-174° C.

(d) 2-Phenyl-4(5)-(4-(4-methoxyphenyl)-3-methylpiperazin-1-yl)methyl!imidazole (Compound135), m.p. 188°-190° C.

EXAMPLE XXXII ##STR70##

To a solution of 6.3 g benzamidine hydrochloride in 60 mL ammoniumhydroxide was added 4.6 g 2-hydroxycyclohexanone. The reaction mixturewas heated to 90° C. for 7 hours in a sealed tube. On cooling to roomtemperature the crystals formed were collected by filtration and afterdrying yielded 3.0 g 2-phenyl-4,5,6,7,-tetrahydrobenzimidazole (Compound136), m.p. 300°-301° C.

To a solution of 50 mg 2-phenyl-5,6,7,8-tetrahydrobenzimidazole in 5 mLcarbon tetrachloride was added 40 mg 1,3-dibromo-5,5-dimethylhydantoin.The mixture was heated to reflux and irradiated with a 500W Tungstenlamp for 30 min. The temperature was lowered momentarily and a solutionof 41 mg 1-(2-pyrimidyl)piperazine was added to the reaction. Themixture was again heated at reflux temperature for 30 min. Then 0.5 mLtriethylamine was added to the reaction and the solution was stirred forI hour at room temperature. The volatiles were evaporated under reducedpressure and the product was purified on silica gel with 10% methanol indichloromethane to yield 28 mg 2-phenyl-7-(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl!-4,5,6,7-tetrahydrobenzimidazole(Compound 137), m.p. 200°-202° C.

EXAMPLE XXXIII

The following compounds were prepared according to the proceduredescribed in Example XXXII.

(a) 2-phenyl-7-(4-benzyl-piperidin-1-yl)-methyl!-4,5,6,7-tetrahydrobenzimidazole(Compound 138), m.p. 189°-191 ° C.

(b) 2-phenyl-7-(N-methyl-N-benzyl)aminomethyl!-4,5,6,7-tetrahydrobenzimidazole(Compound 139), m.p. 181°-183 ° C.

EXAMPLE XXXIV ##STR71##

A solution of 820 mg 2-chloropyrimidine and 1.6 gcis-2,6-dimethylpiperazine in 25 mL toluene was heated at refluxtemperature for 12 hours. The solvent was evaporated, the residue wasbasified with 5% sodium hydroxide and extracted with 2×100mL ofdichloromethane. The combined organic extracts were dried over anhydroussodium sulfate and concentrated to givecis-2,6-dimethyl-1-(2-pyrimidyl)-piperazine. This amine was then used toprepare 2-phenyl-4(5)-(4-(2-pyrimidinyl)-cis-2,6-dimethylpiperazin-1-yl)-methyl!-imidazole(Compound 140), m.p. 130°-135° C., according to the procedures describedin Example VIII.

EXAMPLE XXXV

The following compounds were prepared according to the proceduredescribed in Example XXXIV.

(a) 2-phenyl-4(5)-(4-(2-pyrimidinyl)-trans-2,5-dimethylpiperazin-1-yl)-methyl!-imidazole(Compound 141), m.p. 175°-178° C.

(b) 2-phenyl-4(5)- (8-(2-pyrimidinyl)-3-8-diazabicyclo(3.2.1)octan-3-yl)-methyl!-imidazole (Compound 142), m.p. 190°-194° C.

EXAMPLE XXXVI ##STR72##

A mixture of 5.0 g 1,4-dihydroxy-2-butanone and 7.5 g benzamidinedihydrochloride in 70 mL ammonium hydroxide was heated to 90° C. for 5hours in a sealed tube. The reaction mixture was diluted with 100 mLwater, extracted with 2×50 mL chloroform, dried over anhydrous sodiumsodium sulfate and the solvent removed by evaporation under reducedpressure. The residue was chromatographed on silica gel using 10%methanol in dichloromethane as eluent to yield 1.0 g2-phenyl-4(5)-hydroxyethylimidazole which was reacted with1-(2-pyrimidyl)piperazine according to the procedure Example VIII toyield 2-phenyl-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-ethan-1-yl!-imidazole (Compound 143),m.p. 142°-144° C.

EXAMPLE XXXVII ##STR73##

A mixture of 77 mg 2-phenylimidazole-4(5)-carboxylic acid and 5 mL ofthionyl chloride was heated at reflux temperature for 1 hr. The thionylchloride was removed under reduced pressure to yield 75 mg of2-phenylimidazole-4-carboxylic acid chloride which was then dissolved in5 mL chloroform and treated with 67 mg 1-(2-pyrimidyl)piperazine. Thesolution was heated at reflux temperature for I hr and then 0.5 mLtriethylamine was added. The solution was stirred for another hour,concentrated under reduced pressure and the residue chromatographed onsilica gel using 10% methanol in dichloromethane as eluent to yield 50mg 2-phenyl-4(5)-N-(4-(2-pyrimidinyl)-piperazin-1-yl)-carboxamido!-imidazole(Compound-144), m.p. 231°-232° C.

EXAMPLE XXXVIII

The following compounds were prepared according to the proceduredescribed in Example XXXVII.

(a) 2-phenyl-4(5)-N- (N-methyl-N-benzyl)-carboxamido!-imimazole(Compound 145), characterized as oxalate salt, m.p. 198°-199° C.

(b) 2-phenyl-4(5)-N- (4-benzyl-piperidin-1-yl)-carboxamido!-imidazole(Compound 146), characterized as the hydrochloride salt, m.p. 179°-181°C.

EXAMPLE XXXIX

The following compounds were assayed for D2, D3, and D4 receptor bindingactivity using the assays described above.

    ______________________________________                                        Receptor Binding Activity (Ki. nM)                                                      Dopamine Receptor                                                   Compound No.                                                                              D2          D3      D4                                            ______________________________________                                        45           239        169     5                                             23          1033        8200    2.7                                           24          1029        123     0.85                                          ______________________________________                                    

EXAMPLE XXXX Summary

The effects of 2-phenyl-4(5)-(4-(2-pyrimidyl)-piperazin-1-yl)methyl!-imidazole dihydrochloride(Compound 23) and clozapine were evaluated in the following models oflearning and memory: a step-down passive avoidance task assay and amodified Morris water maze assay separate groups of male Sprague Dawleyrats were pretreated with either Compound 23 or clozapine prior totraining in these tasks. The control compound, clozapine, produced anacquisition deficit in the passive avoidance task at the two highestdoses tested (1.0, 2.0 mg/kg) but produced no significant deficits inretention. Clozapine produced no deficits in the water maze task at thedoses tested. In the step-down passive avoidance assay animals thatreceived the 0.25 mg/kg dose of Compound 23 showed significantimprovement in memory compared to the vehicle group. Likewise in themodified Morris water maze, animals that received the 0.03, 0.25 and the1.0 mg/kg dose of Compound 23 showed significant improvement in taskretention compared to the vehicle group. These data show that Compound23 does not impair learning, but enhances learning in animals.

Method

Non-naive male Sprague Dawley rats (SASCO St Louis) weighing between2000-300 grams, were housed in groups of three in a temperature andhumidity controlled vivarium having a 12 hour light/dark cycle. Animalshad ad lib access to food and water.

Compound 23 was dissolved in 50% Polyethylene glycol (PEG) andadministered in a dose range of 0.03-1.0 mg/kg. Clozapine was dissolvedin 50% PEG and administered in a dose range of from 0.25 to 2mg/kg. Bothdrugs were administered intravenously 5 minutes prior to training inboth learning tasks

Apparatus

Step-Down Passive Avoidance: A step-down passive avoidance platform 4(cm)×7(cm) was placed in the center of an electrified gris floor, whichwas contained within a large (45×45×50 cm) white translucent plexiglasenclosure having a closable lid. The bars of the grip were spaced 1.5 cmapart and were wired to a BRS-LVE shock generator/scrambler which wasset to deliver a 2 mA 6 second shock. Four passive avoidance boxes wereautomated by customer software (Labview) and commercial interfacemodules (National Instruments) connected to a computer The timing anddelivery of the shock as well as the latency to step down and the numberof trims taken to reach criterion during training was under the controlof the computer. All testing was done in the presence of 62 db whitenoise.

Modified Morris Water Maze: A water maze apparatus consisted of acircular tank (120 cm in diameter and 56 cm in height) having a blackinterior. The tank was surrounded by external visual cues whichconsisted of a black and white checkered wall, a black and white stripedwall, a while wall and a blue panel. The tank was filled with water(18°-20° C.) to a height of 52 cm and was divided into four quadrants(North, South, East and West). A black circular plexiglas platform (withblack rubber top) was placed in the northeast quadrant approximately 1cm below the surface of the water. The submerged platform was 51 cm inheight and had a diameter of 9 cm. Training and testing was conducted inthe presence of a 62db white noise source and under dim lightconditions.

Procedure

1. Passive Avoidance:

Acquisition Training: After pretreatment with clozapine, Compound 23 orcontrol (vehicle), the animal was placed on the platform whichautomatically started a timer. When the animal stepped off the platformit automatically received the footshock. Following each shock the animalwas removed from the box and placed in its cage for a one minuteintertrial interval and then returned to the platform. Training wasterminted when the animal remained on the platform for 120 Seconds.Immediately after training the animal was returned to its home cage in avivarium.

Retention Testing: Testing was conduced approximately 24 hours aftertraining, Drug-free animals were placed on the platform in the box inwhich they were trained and the latency to step down onto the unshockedfloor was recorded for one trial. The animal was allowed to a maximum of120 seconds to step down.

2. Modified Morris Water Maze:

Acquisition Training: Acquisition training in this task assay consistedof either four or six training trials. The four trial procedure detectscognitive enhancing effects of drugs while the six trial proceduredetects drugs that produce learning deficits in this task assay Compound23 was tested in the water maze using a four trial procedure andclozapine using a six trial training procedure. Each animal was placedon the platform in the tank for 20 trials separated by an intertrialinterval of 2 minutes. The starting position was pseudo-randomly variedbut was the same order for each animal. During the ITI (intertrialinterval) the animal was dried off and placed near a heat source (heatlamp). The latency to reach the submeged platform on each trial wasmeasured and animals were allowed to remain on the platform for 10seconds once they reach it. Since the platform was submerged just belowthe surface of the water, the animal was required to use the externalvisual cues surrounding the tank (distal cues) to locate the platform.

Retention Training: On the following day, each animal was individuallytested for retention in one trial. All animals were placed in the"SOUTH" starting position and latency to find the submerged platform wasrecorded.

Results

Passive Avoidance: Them were no significant differences for acquisitionbetween the vehicle grup and animals treated with Compound 23. Animalsthat received 0.25 mg/kg dose of Compound 23 remained on the platformfor a significantly longer time during retest than the vehicle animals.Animals that received the 1.0 mg/kg and 2.0 mg/kg doses of clozapineshowed a significant deficit in acquisition compared to the vehiclegroup. There were no significant differences in retention betweenclozapine treated animals and the vehicle group.

Water Maze: The difference between the first trial and the retest trial(latency to locate the platform on the following day) revealedsignificant improvement in retention relative to controls at the 0.03mg/kd, 0.25 mg/kg and the 1.0 mg/kg dose of Compound 23. However, thedifference between the scores of trial 1 and the retest trial foranimals that received clozapine revealed no significant differences.

These results indicate that compound 23 improved memory in mammals.These results fur, her show that compound 23 also enhances learning inmammals. Thus, the compounds of the invention are useful for enhancingcognition in mammals and can be used in methods for enhancing cognition,specifically learning and memory, in mammals.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula: ##STR74## or thepharmaceutically acceptable salts thereof wherein W is nitrogen, COH orCH;R_(a) and R_(b) independently represent hydrogen or alkoxy; X ishalogen or hydrogen m is 0, 1, or 2; and R_(d) is pyridyl, pyrimidinyl,phenylalkyl, or phenyl, each of which is unsubstituted or substitutedwith halogen, hydroxy, lower alkyl or lower alkoxy.
 2. A compound of theformula: ##STR75## or the pharmaceutically acceptable salts thereofwherein W is nitrogen;R_(a) and R_(b) independently represent hydrogenor alkoxy; X is halogen or hydrogen; m is 0, 1, or 2; and R_(d) ispyridyl, pyrimidinyl, phenylalkyl, or phenyl, each of which isunsubstituted or substituted with halogen, hydroxy lower alkyl or loweralkoxy.
 3. A compound of the formula: ##STR76## or the pharmaceuticallyacceptable salts thereof wherein W is CH or COH;R_(a) and R_(b)independently represent hydrogen or alkoxy; X is halogen or hydrogen mis 0, 1, or 2; and R_(d) is pyridyl, pyrimidinyl, phenylalkyl, orphenyl, each of which is unsubstituted or substituted with halogen,hydroxy, lower alkyl or lower alkoxy.
 4. A compound according to claim 1which is selected from the group consisting of2-phenyl-4(5)-(4-(2-pyrimidinyl)-piperazin-1-yl)-propan-1-yl!-imidazole;2-phenyl-4(5)- (4-phenyl-piperazin-1-yl)-propan-1-yl!-imidazole; and2-phenyl-4(5)-(4-hydroxy-4-(4-chlorophenyl)-piperidin-1-yl)-propan-1-yl!-imidazole.